Targeting Inflammation and Alloimmunity in Heart Transplant Recipients with Tocilizumab

使用托珠单抗治疗心脏移植受者的炎症和同种免疫

• 批准号: 10418616
• 负责人: Joren C Madsen
• 金额: $ 199.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418616
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Allografting; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Assessment tool; Autoimmune Diseases; B cell differentiation; Biological Markers; Biopsy; Blocking Antibodies; Cell Count; Cells; Cessation of life; Chronic; Chronic Childhood Arthritis; Clinical; Detection; Diagnostic tests; Disease; Dose; Epitopes; Equilibrium; Experimental Models; FDA approved; FOXP3 gene; Fibrosis; Future; Generations; Heart; Heart Diseases; Heart Transplantation; Heart-Lung Transplantation; Histologic; Human; IL-6 inhibitor; Immune; Immune response; Immune system; Immunity; Immunosuppression; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Interferon Type II; Interleukin 6 Receptor; Interleukin-6; International; Isoantibodies; Jordan; Kidney; Link; Maintenance; Measurement; Mediating; Mediator of activation protein; Memory B-Lymphocyte; Morbidity - disease rate; Natural Killer Cells; Nature; Outcome; Outcome Study; Pathogenicity; Pathway interactions; Patients; Phase; Placebos; Plasmablast; Production; Quality of life; Randomized; Randomized Clinical Trials; Receptor Signaling; Refractory; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Research Personnel; Rheumatoid Arthritis; Risk Assessment; Saline; Societies; T cell response; T-Lymphocyte; Tacrolimus; Testing; Time; Transplant Recipients; Transplantation; Vascular Diseases; allograft rejection; antibody-mediated rejection; base; cell free DNA; cytokine; design; donor-specific antibody; heart allograft; hemodynamics; humanized monoclonal antibodies; immune activation; immunoregulation; improved; improved outcome; inflammatory milieu; insight; isoimmunity; kidney allograft; mycophenolate mofetil; novel; optimal treatments; post-transplant; predictive test; preservation; prevent; primary endpoint; programs; prospective; randomized placebo-controlled clinical trial; response; retransplantation; secondary endpoint; standard of care; tocilizumab; trial design

PROJECT SUMMARY / ABSTRACT Heart transplantation is the optimal therapy for patients with irreversible, end-stage heart disease. However, long-term outcomes are limited by a broad range of inflammatory and immune responses that occur early following transplantation. These include ischemia reperfusion injury, innate immune activation, acute cellular rejection, and antibody-mediated rejection, all of which contribute to late cardiac allograft vasculopathy and fibrosis (chronic rejection). The multifactorial nature of these potent responses explains why current clinical immunosuppressive strategies, designed specifically to target anti-donor T cell responses and acute cellular rejection, are unsuccessful in preventing chronic rejection and achieving acceptable long term survival. Interleukin (IL)-6 is a uniquely pleiotropic cytokine increasingly recognized for its ability to augment and link adaptive, innate, and inflammatory responses. The unique and critical involvement of IL-6 in each of the immune- inflammatory pathways described above makes it an especially attractive cytokine to target. Tocilizumab (Actemra®) is a first-in-class, humanized, monoclonal antibody directed against the IL-6 receptor (IL-6R). It is FDA approved for the treatment of refractory inflammatory diseases. In experimental models, tocilizumab (TCZ) has been shown to skew the Th17/Treg balance in favor of regulatory cell commitment thereby expanding Treg numbers, reducing allograft rejection, and diminishing memory B cell numbers and antibody formation (primary and recall). In human trials, TCZ has proven highly effective in treating antibody-mediated autoimmune disorders. The first use of TCZ in human transplant recipients was recently reported by co-investigator S. Jordan. Not only was it safe and effective in reducing alloantibody levels in highly sensitized kidney allograft recipients, but it was able to improve graft and patient survival in kidney recipients with the most severe form of chronic antibody- mediated rejection. Given the breadth of immune modulation achieved by blocking the IL-6/IL-6R pathway, we hypothesize that the addition of TCZ to conventional immunosuppression in the early post-transplant period will diminish proinflammatory, adaptive and innate immune responses while enhancing regulatory mechanisms. This will initiate a protective/anti-inflammatory milieu that will have long-lasting effects on the host's immune system and allograft resulting in improved long term graft and patient survival. To test this hypothesis, we will conduct a randomized clinical trial to, 1) determine the effect of early TCZ treatment on heart transplant outcomes at a minimum of one year, 2) investigate the effects of TCZ therapy on inflammatory and alloimmune responses in heart transplant recipients, and 3) define the utility of several noninvasive biomarkers as risk assessment, diagnostic, and predictive testing strategies for anticipating outcomes in heart transplant recipients. Our comprehensive and integrated mechanistic studies will allow us to elucidate why therapy succeeded, or failed. Thus, regardless of outcomes, these studies will benefit heart recipients by guiding future trial design.

项目概要/摘要 心脏移植是不可逆的终末期心脏病患者的最佳治疗方法。然而， 长期结果受到早期发生的广泛炎症和免疫反应的限制 移植后。这些包括缺血再灌注损伤、先天免疫激活、急性细胞损伤 排斥反应和抗体介导的排斥反应，所有这些都会导致晚期心脏同种异体移植血管病变和 纤维化（慢性排斥反应）。这些有效反应的多因素性质解释了为什么当前的临床 免疫抑制策略，专门针对抗供体 T 细胞反应和急性细胞反应而设计 排斥反应，但未能成功预防慢性排斥反应并实现可接受的长期生存。 白细胞介素 (IL)-6 是一种独特的多效性细胞因子，因其增强和连接的能力而日益受到认可。 适应性、先天性和炎症反应。 IL-6 在每个免疫过程中的独特且关键的参与 上述炎症途径使其成为特别有吸引力的细胞因子靶点。托珠单抗 (Actemra®) 是一种针对 IL-6 受体 (IL-6R) 的一流人源化单克隆抗体。这是 FDA批准用于治疗难治性炎症性疾病。在实验模型中，托珠单抗 (TCZ) 已被证明可以扭曲 Th17/Treg 平衡，有利于调节细胞承诺，从而扩大 Treg 数量，减少同种异体移植排斥，并减少记忆 B 细胞数量和抗体形成（初级 并回忆）。在人体试验中，TCZ 已被证明在治疗抗体介导的自身免疫性疾病方面非常有效。 联合研究员 S. Jordan 最近报道了 TCZ 在人类移植受者中的首次使用。不仅 它在降低高度敏感的同种异体肾移植受者的同种抗体水平方面是否安全有效？ 能够改善患有最严重形式的慢性抗体的肾受者的移植物和患者的存活率 介导的排斥。鉴于通过阻断 IL-6/IL-6R 途径实现的免疫调节的广度，我们 假设在移植后早期将 TCZ 添加到常规免疫抑制中将 减少促炎性、适应性和先天性免疫反应，同时增强调节机制。这 将启动一个保护/抗炎环境，对宿主的免疫系统产生持久的影响 和同种异体移植可提高移植物和患者的长期存活率。为了检验这个假设，我们将进行 随机临床试验，1) 确定早期 TCZ 治疗对心脏移植结果的影响 至少一年，2) 研究 TCZ 治疗对炎症和同种免疫反应的影响 心脏移植受者，以及 3) 定义了几种非侵入性生物标志物作为风险评估的效用， 用于预测心脏移植受者结果的诊断和预测测试策略。我们的 全面、综合的机制研究将使我们能够阐明治疗成功或失败的原因。 因此，无论结果如何，这些研究都将通过指导未来的试验设计使心脏接受者受益。